Morphological, physiological, and behavioral differences between humans and other primates are partly due to evolutionary innovations that arose in the human lineage. Understanding how and why these innovations evolved is a central motivation for sequencing the chimpanzee and other primate genomes. Interpreting the rapidly growing amounts of comparative sequence and gene expression data will require an integrated conceptual framework that connects molecular and phenotypic evolution. In this project, such framework will be developed in a Drosophila model, which allows genomic and population-genetic data to be combined with genetic crosses and experimental analyses of gene regulation and function. A powerful experimental model will be provided by a sex-specific morphological structure that originated and diversified recently in Drosophila evolution. The first goal of this project is to identify DNA sequence changes and population-genetic forces responsible for the origin and loss of regulatory interactions between genes that control the development of this structure. To accomplish this, biochemical, genetic, and comparative approaches will be combined to reconstruct the evolution of transcription factor binding sites in the regulatory region of a key gene that controls sex-specific differentiation, and examine the effects of natural selection on the sequence and affinity of these sites. The second goal is to identify the genetic and molecular changes responsible for the remodeling of a sex-specific developmental pathway on microevolutionary timescales. Comparative analysis of gene expression will be combined with genetic crosses and transgenic assays to understand how evolutionary changes in gene regulation affect cell differentiation and generate new morphogenetic pathways that shape adult morphology. These approaches will then be extended to a wider range of models to elucidate the genetic and developmental changes responsible for the origin of a novel sex-specific organ, and to test whether convergent morphological changes in different evolutionary lineages were caused by similar changes in development. The final goal of this project is to identify the genes and DNA sequence changes responsible for the recent origin of a unique sex-specific sensory system. This will open the way for understanding the molecular-genetic and neurobiological mechanisms of evolutionary changes in behavior. PUBLIC HEALTH RELEVANCE: The fundamental principle of sexual development - that sex-specific regulators act by modulating the output of other developmental pathways - is shared by all animals, including humans. Model system research that elucidates the molecular mechanisms and evolution of sexual differentiation will lead to a better understanding of the origin and development of sex-specific traits in humans, opening the way for designing drugs and prophylactic treatments that target male- or female-specific developmental pathways.